RRC ID 45321
Author Ogawa F, Amano H, Eshima K, Ito Y, Matsui Y, Hosono K, Kitasato H, Iyoda A, Iwabuchi K, Kumagai Y, Satoh Y, Narumiya S, Majima M.
Title Prostanoid induces premetastatic niche in regional lymph nodes.
Journal J Clin Invest
Abstract The lymphatic system is an important route for cancer dissemination, and lymph node metastasis (LNM) serves as a critical prognostic determinant in cancer patients. We investigated the contribution of COX-2-derived prostaglandin E2 (PGE2) in the formation of a premetastatic niche and LNM. A murine model of Lewis lung carcinoma (LLC) cell metastasis revealed that COX-2 is expressed in DCs from the early stage in the lymph node subcapsular regions, and COX-2 inhibition markedly suppressed mediastinal LNM. Stromal cell-derived factor-1 (SDF-1) was elevated in DCs before LLC cell infiltration to the lymph nodes, and a COX-2 inhibitor, an SDF-1 antagonist, and a CXCR4 neutralizing antibody all reduced LNM. Moreover, LNM was reduced in mice lacking the PGE2 receptor EP3, and stimulation of cultured DCs with an EP3 agonist increased SDF-1 production. Compared with WT CD11c+ DCs, injection of EP3-deficient CD11c+ DCs dramatically reduced accumulation of SDF-1+CD11c+ DCs in regional LNs and LNM in LLC-injected mice. Accumulation of Tregs and lymph node lymphangiogenesis, which may influence the fate of metastasized tumor cells, was also COX-2/EP3-dependent. These results indicate that DCs induce a premetastatic niche during LNM via COX-2/EP3-dependent induction of SDF-1 and suggest that inhibition of this signaling axis may be an effective strategy to suppress premetastatic niche formation and LNM.
Volume 124(11)
Pages 4882-94
Published 2014-11-1
DOI 10.1172/JCI73530
PII 73530
PMID 25271626
PMC PMC4347225
MeSH Animals Antineoplastic Agents / pharmacology Carcinoma, Lewis Lung / immunology Carcinoma, Lewis Lung / metabolism Carcinoma, Lewis Lung / secondary* Celecoxib Cell Line, Tumor Chemokine CXCL12 / metabolism Cyclooxygenase 2 / metabolism Cyclooxygenase 2 Inhibitors / pharmacology Dendritic Cells / immunology Dinoprostone / physiology* Drug Screening Assays, Antitumor Gene Knockout Techniques Lung Neoplasms / immunology Lung Neoplasms / metabolism Lung Neoplasms / pathology* Lymph Nodes / immunology Lymph Nodes / pathology* Lymphangiogenesis Lymphatic Metastasis Male Mice, Knockout Neoplasm Transplantation Pyrazoles / pharmacology Receptors, CXCR4 / metabolism Receptors, Prostaglandin E, EP3 Subtype / genetics Receptors, Prostaglandin E, EP3 Subtype / metabolism Signal Transduction Sulfonamides / pharmacology T-Lymphocytes, Regulatory / immunology
IF 11.864
Times Cited 37
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